The present invention concerns combination chemotherapy regimes for the treatment of hyperproliferative disorders, and formulations useful for carrying out the same.
Fenretinide [HPR; all-trans-N-(4-hydroxyphenyl)retinamide; CAS Registry number 65646-68-6] is currently believed to effect cytotoxicity in cancer cells by generating reactive oxygen species. See, e.g., D. Delia et al., Carcinogenesis 18, 943-948 (1997); N. Oridate et al., J. Natl. Cancer Inst. 89, 1191-1198 (1997).
U.S. Pat. No. 4,665,098 to Gibbs describes pharmaceutical compositions of fenretinide as useful for the treatment of breast and bladder cancer.
U.S. Pat. No. 5,821,072 to Schwartz et al. provides methods for screening protein kinase C inhibitors capable of potentiating apoptosis in tumor cells, along with methods for screening antitumor therapeutic agents suitable for combination therapy with a protein kinase C inhibitor capable of potentiating apoptosis in tumor cells.
The present invention is based on the unexpected discovery that fenretinide at appropriate doses generates increased and sustained ceramide in human cancer cell lines. Thus, the cytostatic or cytotoxic activity against hyperproliferative disorders (including neoplastic and nonneoplastic hyperproliferative disorders as defined below) of fenretinide and other such retinoic acid derivatives that generate ceramide can be enhanced by administering an agent that manipulates cellular metabolism and cellular control of ceramide-generated cytotoxicity (e.g., a ceramide degradation inhibitor). Such agents include, but are not limited to, glucosyl ceramide synthase inhibitors, sphingosine-1-phosphate synthesis inhibitors, and protein kinase C inhibitors, which may be administered alone or in combination with one another. Specific examples are given below. Preferably, the retinoic acid derivative is given in an amount effective to produce necrosis, apoptosis, or both in the tumor cell, and the ceramide degradation inhibitor is given in an amount effective to increase the necrosis, apoptosis or both produced in the tumor cell over that which would be produced by the retinoic acid derivative alone, or that expected to be produced by the sum of that produced by the retinoic acid derivative and the ceramide degradation inhibitor when given separately (this includes the situation where the combination of both compounds produce an efficacous activity at amounts of the compounds that produce no activity when administered separately).
A method of treating a hyperproliferative disorder in a subject in need of such treatment comprises administering to the subject, in combination, a treatment effective amount of: (a) a retinoic acid derivative that generates ceramide such as fenretinide or a pharmaceutically acceptable salt thereof; and (b) a glucosylceramide synthesis inhibitor (including the pharmaceutically acceptable salts thereof) such as 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol or a pharmaceutically acceptable salt thereof. The glucosylceramide synthesis inhibitor is administered in an amount effective to enhance the activity of the retinoic acid derivative, such that the two compounds together have an efficacious activity. Preferably, the retinoic acid derivative is given in an amount effective to produce necrosis, apoptosis, or both in the tumor cell, and the glucosylceramide synthesis inhibitor is given in an amount effective to increase the necrosis, apoptosis or both produced in the tumor cell over that which would be produced by the retinoic acid derivative alone, or that expected to be produced by the sum of that produced by the retinoic acid derivative and the glucosylceramide synthesis inhibitor when given separately. Other compounds including the compounds described herein may also be administered.
Also disclosed is a method of treating a hyperproliferative disorder in a subject in need of such treatment which comprises administering to the subject, in combination, a treatment effective amount of: (a) a retinoic acid derivative that generates ceramide such as fenretinide or a pharmaceutically acceptable salt thereof; and (b) a sphingosine-1-phosphate synthesis inhibitor such as D-erythro-N,N-dimethylsphingosine or a pharmaceutically acceptable salt thereof. The sphingosine-1-phosphate synthesis inhibitor is administered in an amount effective to enhance the activity of the retinoic acid derivative, such that the two compounds together have an efficacious activity. Preferably, the retinoic acid derivative is given in an amount effective to produce necrosis, apoptosis, or both in the tumor cell, and the sphingosine-1-phosphate synthesis inhibitor is given in an amount effective to increase the necrosis, apoptosis, or both produced in the tumor cell over that which would be produced by the retinoic acid derivative alone, or that expected to be produced by the sum of that produced by the retinoic acid derivative and sphingosine-1-phosphate synthesis inhibitor when given separately.
Also disclosed is a method of treating a hyperproliferative disorder in a subject in need of such treatment, the method comprising administering to the subject, in combination, a treatment effective amount of: (a) a retinoic acid derivative that generates ceramide such as fenretinide or a pharmaceutically acceptable salt thereof, and (b) a protein kinase C inhibitor such as L-threo-dihydrosphingosine or a pharmaceutically acceptable salt thereof. The protein kinase C inhibitor is administered in an amount effective to enhance the activity of the retinoic acid derivative, such that the two compounds together have an efficacious activity. Preferably, the retinoic acid derivative is given in an amount effective to produce necrosis, apoptosis or both, in the tumor cell, and the protein kinase C inhibitor is given in an amount effective to increase the necrosis, apoptosis or both produced in the tumor cell over that which would be produced by the retinoic acid derivative alone, or that expected to be produced by the sum of that produced by the retinoic acid derivative and protein kinase C inhibitor when given separately.
Also disclosed is a method of treating a hyperproliferative disorder in a subject in need of such treatment, comprising administering to said subject, in combination, a treatment effective amount of: (a) a ceramide-generating retinoid or a pharmaceutically acceptable salt thereof; and (b) at least two (e.g., 2 or 3) compounds selected from the group consisting of (i) glucosylceramide synthesis inhibitors, (ii) sphingosine-1-phosphate synthesis inhibitors, and (iii) protein kinase C inhibitors. The at least two compounds are administered in an amount effective to enhance the activity of the retinoid, such that the compounds together have an efficacious activity. The at least two compounds may be from the same or a different category. In one embodiment, the at least two compounds comprise a glucosylceramide synthesis inhibitor and a sphingosine-1-phosphate synthesis inhibitor. In another embodiment, the at least two compounds comprise a glucosylceramide synthesis inhibitor and a protein kinase C inhibitor. In another embodiment, the at least two compounds comprise a sphingosine-1-phosphate synthesis inhibitor and a protein kinase C inhibitor. In another embodiment, the at least two compounds comprise a glucosylceramide synthesis inhibitor, a sphingosine-1-phosphate synthesis inhibitor, and a protein kinase C inhibitor. Preferably, the retinoic acid derivative is given in an amount effective to produce necrosis, apoptosis or both in the tumor cell, and the at least two other compounds are given in an amount effective to increase the necrosis, apoptosis or both produced in the tumor cell over that which would be produced by the retinoic acid derivative alone, or that expected to be produced by the sum of the that produced by the retinoic acid derivative and the at least two other compounds when given separately.
Formulations comprising the aforesaid combinations of compounds in a single pharmaceutical carrier or vehicle, for carrying out the foregoing treatments, are also an aspect of the instant invention.
The use of the foregoing compounds for the preparation of a medicament for carrying out the aforesaid treatments are also an aspect of the instant invention.
The foregoing and other objects and aspects of the present invention are explained in detail in the drawings herein and the specification set forth below.